Postnatal activity of Hedgehog signaling functions in regulation of stem cell physiology and tissue regeneration1-5. Following bacterial injury of the bladder, for example, Sonic hedgehog (Shh) produced in cells of the basal urothelium elicits production of factors from stromal cells, which in turn stimulate proliferation and differentiation of urothelial cells. This epithelial/stromal feedback leads to regeneration of the urothelium and restoration of its normal function2. In this regenerative response to murine urinary tract infection, the Shh-expressing basal cells function as stem cells by proliferating and supplying the progenitor cells that give rise to differentiated cells and ultimately replenish the injured urothelium2.
These Shh-expressing basal stem cells also give rise to invasive urothelial carcinoma in a murine chemical carcinogenesis model utilizing the procarcinogen Nbutyl-N-4-hydroxybutyl nitrosamine (BBN)6. Marking of Shh-expressing basal cells in this model invariably marks tumors, whereas ablation of these cells decisively abrogates tumor formation. Surprisingly, although this combination of positive and negative evidence clearly demonstrates that basal urothelial stem cells expressing Shh are the exclusive cell of origin for invasive bladder cancer, expression of Shh is lost by the time invasive carcinomas are formed6. One possible explanation for this observation is that loss of Shh expression may somehow promote tumor progression. This effect, however, would represent a novel protective role for Hh pathway activity, as mutational activation of the Hh pathway is causative in the primary cells of basal cell carcinoma and medulloblastoma7-9, and ligand-dependent pathway activity in stroma has been thought to promote growth of pancreatic cancer10,11.